The overall goal of this project is to understand the biological mechanisms underlying the addictive diseases, focusing on three addictions that pose enormous public health problems and carry devastating morbidity and mortality: addictions to heroin and other related opiates, cocaine, and alcohol. Pursuing this goal has led not only to the development of safe and effective treatments, but in parallel, has led to the elucidation of fundamental aspects of normal human physiology, and also the neurobiological mechanisms underlying addictive diseases which continues to guide the development of new treatments.1 A related goal is to study the natural history of each of these three addictive diseases and how other diseases which are very prevalent in the addict population, including hepatitis B, delta, C, HIV-1 infection, and AIDS can alter this natural history. Studies of the disposition, metabolism, excretion and pharmacokinetics of both drugs of abuse and actual or potential treatment agents are also an essential component of the ongoing clinical research of this project. We propose to define the neuroendocrine disturbances associated with cocaine addiction (alone, complicated with, and in contrast to alcohol, nicotine, and/or opioid exposure), and to evaluate existing and potential pharmacological treatments for addictions from the perspective of their ability to protect against, and/or correct these disturbances.